Targeting tumor glycolysis in pancreatic cancer - volumetric and functional tumor response assessment in an orthotopic mouse tumor model

Pancreatic cancer is one of the most lethal human malignancies with a dismal prognosis and, until today, no loco-regional therapeutic options. The main objective of this study is to use the combination of functional bioluminescence imaging (BLI) and small animal ultrasound imaging (SAUI) in a xenograft mouse model in order to demonstrate the efficacy of loco-regional and systemic delivery of the anti-glycolytic agent 3-Bromopyruvate (3-BrPA). Male athymic nude mice (5 weeks old, N=15) were used to generate orthotopic xenografts. 1.5 x 106 MiaPaCa-2 cells, stably transfected with a luciferase reporter gene, were surgically implanted into the tail of the pancreas. 7 days after surgery, mice were subjected to BLI and SAUI to confirm the localization of the tumor and to measure baseline tumor volume [calculated as prolate spheroid] and viability [BLI signal intensity in steradian]. N=3 mice received a onetime, ultrasound-guided, intra-tumoral (i.t.) injection and N=6 mice received daily intra-peritoneal (i.p.) injections (3 cycles, 5 days each) with a 1.75 mM solution of 3-BrPA vs. saline control for each method (N=6). Follow-up imaging was carried out to estimate tumor response. Normalized BLI signal was correlated with SAUI measurements using a linear regression model. Orthotopic tumor viability and formation was confirmed on BLI and SAUI in all animals, respectively. The signal intensity on baseline BLI (mean of 3.4 x 107 [1.4-4.9 x 107 p/s/cm2/Sr]) correlated well with baseline tumor volume (mean of 122mm3 [98-163mm3]) (R2=.88). All animals in the control group showed tumor progression (mean tumor volume of 864mm3 and mean BLI signal increase by 294%). All animals treated i.p. responded to the drug (mean BLI signal decrease by 82%, tumor volume increase to a mean of 322mm3). All animals treated i.t. responded on BLI (mean signal decrease by 61%) and no volume increase was observed. Efficacy of loco-regional and systemic therapy with 3-BrPA in a xenograft mouse model of pancreatic cancer can be assessed using functional BLI and volumetric SAUI. Targeting tumor glycolysis with 3-BrPA is promising and must be further explored.